RESUMEN
We report herein the synthesis and structure-activity relationships (SAR) of a series of benzyl ether compounds as an S1P1 receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P1 and S1P3 agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P1/S1P3 selectivity. These changes of the S1P1 and S1P3 agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P1 X-ray crystal structure and S1P3 homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P1/S1P3 selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats.
Asunto(s)
Éteres/química , Inmunosupresores/química , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Sitios de Unión , Éteres/farmacocinética , Éteres/uso terapéutico , Rechazo de Injerto/prevención & control , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Masculino , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Ratas , Ratas Endogámicas Lew , Receptores de Lisoesfingolípidos/metabolismo , Relación Estructura-Actividad , Trasplante HomólogoRESUMEN
A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.
Asunto(s)
Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Fenilacetatos/química , Fenilacetatos/farmacología , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacología , Sitios de Unión , Óxidos S-Cíclicos/aislamiento & purificación , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Fenilacetatos/aislamiento & purificación , Inhibidores de Fosfodiesterasa 4/aislamiento & purificaciónRESUMEN
Phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of pulmonary inflammatory diseases, but their clinical use was dose-limited by mainly gastric adverse effects. Recent studies suggested PDE4B-selective inhibitors over PDE4D are supposed to display a wider therapeutic index than subtype non-selective PDE4 inhibitors such as roflumilast. Compound A was identified as an orally active PDE4B-selective inhibitor over PDE4D both in humans (80-fold selective) and mice (29-fold selective). In this study, the therapeutic effects of compound A and roflumilast were evaluated on lipopolysaccaride (LPS) injection-induced plasma TNF-α elevation and on LPS inhalation-induced pulmonary neutrophilia in mice. The inhibitory effect on gastric emptying in mice was evaluated as a gastric adverse effect. The therapeutic index for TNF-α production (TI(TNF) = ID50 in gastric emptying / ID50 in LPS injection-induced plasma TNF-α elevation) of compound A was larger than roflumilast (9.0 and 0.2, respectively), whereas the therapeutic index for pulmonary neutrophilia (TI(Neu) = ID50 in gastric emptying / ID50 in LPS inhalation-induced pulmonary neutrophilia) of compound A was comparable to roflumilast (1.0 and 0.5, respectively). In conclusion, the TI(Neu) of compound A was not superior compared to that of roflumilast in spite of its high selectivity for PDE4B over PDE4D in mice.
Asunto(s)
Aminopiridinas/uso terapéutico , Benzamidas/uso terapéutico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Trastornos Leucocíticos/tratamiento farmacológico , Neutrófilos , Fenilacetatos/uso terapéutico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Neumonía/tratamiento farmacológico , Administración Oftálmica , Aminopiridinas/administración & dosificación , Aminopiridinas/efectos adversos , Animales , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Ciclopropanos/administración & dosificación , Ciclopropanos/efectos adversos , Ciclopropanos/uso terapéutico , Vaciamiento Gástrico/efectos de los fármacos , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Humanos , Trastornos Leucocíticos/inducido químicamente , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos BALB C , Infiltración Neutrófila , Fenilacetatos/efectos adversos , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Inhibidores de Fosfodiesterasa 4/efectos adversos , Neumonía/inducido químicamente , Factor de Necrosis Tumoral alfa/sangreRESUMEN
5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16 mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50=0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.).
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Sitios de Unión , Dominio Catalítico , Células Cultivadas , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Activación Enzimática/efectos de los fármacos , Humanos , Lipopolisacáridos/toxicidad , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/tratamiento farmacológico , Ratones , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Piridonas/uso terapéutico , Pirimidinas/química , Pirimidinas/uso terapéutico , Bazo/citología , Bazo/efectos de los fármacos , Bazo/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5 nM) and TNF-α production in mouse splenocytes (IC50=9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.
Asunto(s)
Antiinflamatorios/química , Bencenoacetamidas/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Óxidos S-Cíclicos/química , Inhibidores de Fosfodiesterasa 4/química , Pirimidinas/química , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/uso terapéutico , Bencenoacetamidas/metabolismo , Bencenoacetamidas/uso terapéutico , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Óxidos S-Cíclicos/metabolismo , Óxidos S-Cíclicos/uso terapéutico , Humanos , Lipopolisacáridos/toxicidad , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/patología , Ratones , Inhibidores de Fosfodiesterasa 4/metabolismo , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Unión Proteica , Pirimidinas/metabolismo , Pirimidinas/uso terapéutico , Bazo/citología , Bazo/metabolismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The total synthesis of siomycin A (1), a representative compound of the thiostrepton family of peptide antibiotics, was achieved by incorporating the five synthetic segments A (2), B (3), C (4), D (5), and E (6). The dehydropiperidine segment A (2) was esterified with the dihydroquinoline segment C (4), and the subsequent coupling with the beta-phenylselenoalanine dipeptide segment D (5) at the segment C portion followed by lactamization between the segments A and D gave segment A-C-D (27). This was amidated with the pentapeptide segment B (3) at the segment A portion followed by one-pot cyclization (between segments A and B) and elongation (with the beta-phenylselenoalanine dipeptide segment E (6) at the segment A portion), thus furnishing siomycin A (1).
Asunto(s)
Péptidos/síntesis química , Aminas/química , Ciclización , Compuestos Epoxi/química , Hidrogenación , Isomerismo , Modelos Químicos , Estructura Molecular , Péptidos/química , Compuestos de Selenio/químicaRESUMEN
The five practical segments for the total synthesis of siomycin A, that is, the dehydropiperidine segment A (5), the pentapeptide segment B (3), the dihydroquinoline segment C (6), and the beta-phenylselenoalanine dipeptide segments D (7) and E (4), were synthesized. Segment A (5) was constructed by the coupling of the azomethine ylide and the chiral sulfinimine, followed by the stereoselective reduction of the six-membered imine function. Segment B (3) was synthesized by the phenylselenylation of the beta-lactone, stereoselective vinylzinc addition to the chiral sulfinimine, and oxazoline-thioamide conversion. Segment C (6) was prepared by the one-pot olefination of the tetrahydroquinoline N-oxide using triflic anhydride and triethylamine, stereoselective reduction of the methyl ketone function, and regioselective Yb(OTf)(3)-catalyzed epoxide opening by the amino group. Segments D (7) and E (4) were synthesized by coupling of the properly protected beta-phenylselenoalanines.